Retinoid receptors and other nuclear receptors (that include the steroid, thyroid and vitamin D hormone receptors and other “orphan” receptors without known ligands) are targets for drug development. It is thought that retinoic acid (RA) and synthetic retinoids act as ligand-dependent transcription factors with different members of nuclear retinoid receptors to control gene transcription responsible for cellular proliferation, differentiation, development and cell death. Two classes of nuclear retinoid receptors (RARs and RXRs) have been identified so far, and each has several different subtypes (α, β, γ). Both (E)-RA and (9Z)-RA bind to RARs and activate transcription mediated by RAR/RXR heterodimers, but (9Z)-RA is the only known natural ligand for the RXRs which mediate transcription by forming homodimers or heterodimers.
Recent advances in chemoprevention have heightened interest in the use of RXR-selective retinoids in several types of solid organ tumors, and major therapeutic successes have been demonstrated with retinoids in certain lymphomas. Bexarotene (a RXR-selective retinoid) is approved for the treatment of Cutaneous T cell Lymphoma.
The wide range of benefits from the uses of these retinoid compounds, including uses in treating, preventing or ameliorating non-neoplastic conditions or disorders, have not been fully identified or explored. Although RAR-selective compounds were known to induce skin hyperplasia, an indicator of retinoid activity in the skin, RXR-selective compounds were previously shown not to be effective inducers of epidermal hyperplasia, considering them silent partners in the RAR-RXR heterodimer with unlikely clinical utility in non-neoplastic skin conditions. See, for example, Thacher, S. M., et al., Receptor Specificity of Retinoid-Induced Epidermal Hyperplasia: Effect of RXR-Selective Agonists and Correlation with Topical Irritation, JPET 282:528-534, 1997. The present invention fulfills a need for new and beneficial uses of retinoid compounds, particularly RXR-selective compounds, for non-neoplastic skin conditions or disorders, as previously not described or realized.